HIV infection is associated with increased incidences of multiple tumors, many of which are associated with oncogenic tumor viruses like KSHV, Epstein-Barr virus (EBV), or human papillomavirus (HPV). HIV infection is a worldwide health issue affecting both developed and developing nations. Infection with HIV causes a depletion of CD4+ T cells, which leads to immune suppression. Kaposi's sarcoma (KS), induced by KSHV, is the most common neoplasm seen among HIV infected individuals. In addition to KS, KSHV is also associated with primary effusion lymphomas (PELs) and multicentric Castleman's disease (MCD). Currently, there are no therapeutic vaccines that protect against KSHV infection or drugs that can cure infected cells of KSHV. Like all herpesviruses, KSHV establishes life-long latency in the host. Hence, primary infection represents the beginning of KSHV's sojourn in the human host. The goal of this proposal is to use a novel approach to develop a vaccine against KSHV infection. We propose to use rhesus monkey rhadinovirus (RRV) as an animal model system for KSHV infection. RRV was originally isolated from rhesus macaques, is very closely related to KSHV and most of the eighty open reading frames (ORFs) of RRV share high homology with the corresponding ORFs of KSHV. RRV is useful to the study of KSHV pathogenesis because unlike KSHV, RRV has a permissive lytic system and the virus can be grown to high titers. RRV has been shown to induce B cell hyperplasia and lymphoma in the context of SIV co-infection. In addition, the availability of the natural animal host, the rhesus macaque can serve as an invaluable animal model system to determine whether vaccination using a recombinant RRV can protect against challenge with wild-type RRV. The community that will benefit from this research includes all HIV-infected patients at a global level and well as the HIV-negative population. According to the UNAIDS 2008 Report, around 30.8 million adults and 2 million children were living with HIV at the end of 2007. KSHV-associated cancers are much more prevalent in the HIV-infected population and KS is the most frequent cancer seen in this population. Hence, our proposal to develop a KSHV vaccine may have a significant impact. The project represents an interdisciplinary collaboration between Dr. Blossom Damania and Dr. Dirk Dittmer's laboratories in the Department of Microbiology &Immunology and the Lineberger Cancer Center at UNC-Chapel Hill, and Dr. Roland Desrosiers at the New England Primate Research Center at Harvard Medical School. Thus, this collaborative project integrates the PI's expertise in KSHV and RRV, with Dr. Desrosiers'expertise in vaccine design and development, and the use of primate infection models for RRV. PUBLIC HEALTH RELEVANCE: HIV infection is associated with increased incidences of multiple tumors, many of which are associated with oncogenic tumor viruses like KSHV, Epstein-Barr virus (EBV), or human papillomavirus (HPV). HIV infection is a worldwide health issue affecting both developed and developing nations. Infection with HIV causes a depletion of CD4+ T cells, which leads to immune suppression. Kaposi's sarcoma (KS), induced by KSHV, is the most common neoplasm seen among HIV infected individuals. In addition to KS, KSHV is also associated with primary effusion lymphomas (PELs), and multicentric Castleman's disease (MCD). Currently, there are no therapeutic vaccines that protect against KSHV infection or drugs that can cure infected cells of KSHV. Like all herpesviruses, KSHV establishes life-long latency in the host. Hence, primary infection represents the beginning of KSHV's sojourn in the human host. The goal of this proposal is to use a novel approach to develop a vaccine against KSHV infection. We propose to use rhesus monkey rhadinovirus (RRV) as an animal model system for KSHV infection. RRV was originally isolated from rhesus macaques, is very closely related to KSHV and most of the eighty open reading frames (ORFs) of RRV share high homology with the corresponding ORFs of KSHV. RRV is useful to the study of KSHV pathogenesis because unlike KSHV, RRV has a permissive lytic system and the virus can be grown to high titers. RRV has been shown to induce B cell hyperplasia and lymphoma in the context of SIV co-infection. In addition, the availability of the natural animal host, the rhesus macaque can serve as an invaluable animal model system to determine whether vaccination using a recombinant RRV can protect against challenge with wild-type RRV. The community that will benefit from this research includes all HIV-infected patients at a global level and well as the HIV-negative population. According to the UNAIDS 2008 Report, around 30.8 million adults and 2 million children were living with HIV at the end of 2007. KSHV-associated cancers are much more prevalent in the HIV-infected population and KS is the most frequent cancer seen in this population. Hence, our proposal to develop a KSHV vaccine may have a significant impact. The project represents an interdisciplinary collaboration between Dr. Blossom Damania and Dr. Dirk Dittmer's laboratories in the Department of Microbiology &Immunology and the Lineberger Cancer Center at UNC-Chapel Hill, and Dr. Roland Desrosiers at the New England Primate Research Center at Harvard Medical School. Thus, this collaborative project integrates the PI's expertise in KSHV and RRV, with Dr. Desrosiers'expertise in vaccine design and development, and the use of primate infection models for RRV.